When blood vessels are injured by physical traumas including surgical interventions, bleedings will occur. Dependent on the extent of the injury, bleedings may result in losses of blood which can affect the normal function of the individual or, in cases of bleedings occurring in osseous non-expandable cavities, the accumulation of extravasated blood may cause damages of soft tissues due to increased pressure. If bleedings are left alone they will eventually be arrested by a normally occurring physiological process characterised by a chain of events involving the combined activity of vascular, platelet, and plasma factors. This process is referred to as a physiological haemostasis, an important element of which is blood coagulation which is described below. In the case of a minor superficial bleeding, this physiological haemostasis is adequate for the arrest.
Blood coagulation may be described as occurring in the following steps.
(1) The formation of an activator of prothrombin, which is a precursor of the plasma serine protease thrombin. The prothrombin activator is a complex of an enzyme factor Xa and two cofactors: factor Va and procoagulant phospholipids, both present on the surface of activated platelets. Furthermore, the presence of calcium ions is necessary for the function of the activator.
(2) The cleavage by the above activator system of prothrombin into two fragments, one of which is the enzyme thrombin.
(3) The conversion by thrombin of the plasma precursor fibrinogen to the clotting substance fibrin. This process involves several steps, the first of which comprises the cleavage of small peptides from fibrinogen, whereby fibrin monomers are formed, which then polymerise to form insoluble fibrin polymers. As a final step, thrombin activates the plasma factor XIII, an enzyme that catalyses the formation of covalent bonds between fibrin molecules, thereby cross-linking the molecules to form a firm clot resistant to dissolution.
In the above step (1) leading to the formation of the prothrombin activator system, several plasma proteases are involved in a cascade of proteolytic events. These blood coagulation factors are currently referred to by using Roman numerals, such as factor VII, factor VIII, factor IX, factor XI, and factor XII. The cascade involves sequential proteolytic activations of the next enzyme in the cascade. Thus activated blood coagulation factors are designated by their Roman numerals followed by an “a”, such as factor Vila, factor Villa, factor XIIIa or factor IXa.
However, bleedings emerging from more extensive injuries, especially such injuries which involve larger arteries or when seeping bleedings occur from larger mucosal surfaces or in cavities without drainage, require the adoption of surgical and/or medical haemostatic measures. Surgical arrest of bleeding comprises ligation or suture of disrupted blood vessels, plugging by using tampons in cavities, coagulating tissue surfaces including their exposed disrupted blood vessels by heated instruments or by the application of cauterising agents or heated air. Surgical haemostasis may also be aided by the application at the injured site of appropriately sized blocks, plates, or films of biologically absorbable haemostatic sponges. Powders or flakes, which are typically wetted before application to create a paste, have also been used.
In this context, the term “sponge” is understood to mean a porous structure characterised in that the structure is reticulate and has an inner surface considerably larger than its outer surface, that it contains hollow spaces within the reticulate structure, and that it can absorb many times its own weight in liquids.
Such haemostatic sponges or compositions are useful for enhancing the arrest of bleedings in several instances of surgical interventions or other injuries such as in surgery of large abdominal organs (liver, spleen, or intestines); in lung surgery; in neurosurgery to prevent pressure damages of the cerebral or nerve tissues; in orthopaedic surgery during which extensive haemorrhages frequently occur which are difficult to arrest by other means; in vascular surgery to arrest seeping bleedings from the sites of suturing; in oral or dental surgery such as extraction of teeth; and in nose-bleeding (epistaxis).
It is currently believed that the haemostatic effect (or mode of action) of a sponge is linked to sponge porosity and the sponge's ability to absorb blood. A conventional gelatine sponge adheres to the bleeding site and absorbs approximately 45 times its own weight. Due to the uniform porosity of a conventional gelatine sponge, blood platelets are caught and the coagulation cascade is activated transforming soluble fibrinogen into a net of insoluble fibrin which stops the bleeding. Thus, a good capacity to absorb is believed essential for the mode of action of conventional gelatine sponges.
As mentioned above, a conventional gelatine sponge's ability to act as a haemostat is related to its ability to absorb, whereby the volume of the sponge inevitably will increase. However, swelling of the sponge can lead to adverse events if the sponge is not used according to the instructions. Normally, the instruction for use includes the phrase: “When placed into cavities or closed tissue spaces, minimal preliminary compression is advised and care should be exercised to avoid overpackaging. The gelatine sponge may swell to its original size on absorbing fluids creating the potential for nerve damage”. Nevertheless, adverse events have taken place in the past, and the UK Medical Device Agency as well as the FDA have paid much attention to this drawback of conventional sponges.
Accordingly, there is a need for haemostatic sponges which, while maintaining a sufficient blood arresting (haemostatic) effect, swell to a much lesser extent than conventional haemostatic sponges. Evidently, such sponges would constitute a safer product.
The present invention deals with haemostatic compositions with improved properties and methods of producing said compositions.
The inventors of the present invention have surprisingly found that the haemostatic compositions of the present invention are more efficient in arresting bleeding than conventional compositions, such as Surgifoam®, Surgifoam® powder or Gelfoam® powder, i.e. the haemostatic properties of the compositions according to the invention are improved compared to conventional compositions.
Furthermore, the present inventors have solved the above-mentioned problem of swelling by incorporating hyaluronic acid (HA), or a derivative thereof, into or onto a haemostatic composition.
Surprisingly, it has been found that swelling of a haemostatic sponge according to the present invention is considerably reduced compared to conventional sponges, such as Surgifoam®. Evidently, the haemostatic sponges described herein are safer to use than conventional sponges.
The above-mentioned properties, i.e. decreased tendency to swell and improved haemostatic properties, are attributed to the presence of HA, or derivatives thereof. HA, and derivatives thereof, are known to confer anti-adhesive properties to sponges as described in e.g. Laurent et al. Am J Otolaryngol; 7:181-186, 1986; U.S. Pat. No. 6,548,081; U.S. Pat. No. 6,099,952; U.S. Pat. No. 5,503,848; U.S. Pat. No. 5,700,476; EP 1 022 031 A1; WO 94/17840. Nevertheless, the surprising effects of conferring improved haemostatic properties to the composition and reducing the ability of a sponge to swell, have not been described in any of the above-identified prior art documents.
In summary, the haemostatic compositions and in particular a haemostatic sponge of the present invention contain numerous advantages as compared to conventional and commercially available haemostatic compositions and sponges:
i) reduced swelling, thereby rendering the sponge safer to use,
ii) improved haemostatic properties, and
iii) improved anti-adhesive properties, thereby reducing post-operative adhesion of tissues.